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In two recent reports in Science, James Chen and colleagues provide compelling evidence that detection of cytosolic DNA triggers the production of a novel second messenger, cyclic GMP-AMP (cGAMP), which in turn activates a signaling pathway that induces type I interferons (IFNs) in a STING-dependent manner. They further unravel a key role for a so far uncharacterized murine protein E330016A19 (human homolog: C6ORF150), now termed cGAMP synthetase (cGAS), to act as the DNA sensor that generates cGAMP.

The presence of nucleic acids in the cytosol alerts the cell to viral infection or damaged self. The oligoadenylate synthase (OAS) proteins and cyclic GMP–AMP synthase (cGAS) are enzymes that detect this danger and promote antiviral immunity. Recent structural studies reveal that these enzymes have a common mechanism of action and probably the same evolutionary origin. Supplementary information The online version of this article (doi:10.1038/nri3719) contains supplementary material, which is available to authorized users., Recent discoveries in the field of innate immunity have highlighted the existence of a family of nucleic acid-sensing proteins that have similar structural and functional properties. These include the well-known oligoadenylate synthase (OAS) family proteins and the recently identified OAS homologue cyclic GMP–AMP (cGAMP) synthase (cGAS). The OAS proteins and cGAS are template-independent nucleotidyltransferases that, once activated by double-stranded nucleic acids in the cytosol, produce unique classes of 2′–5′-linked second messenger molecules, which — through distinct mechanisms — have crucial antiviral functions. 2′–5′-linked oligoadenylates limit viral propagation through the activation of the enzyme RNase L, which degrades host and viral RNA, and 2′–5′-linked cGAMP activates downstream signalling pathways to induce de novo antiviral gene expression. In this Progress article, we describe the striking functional and structural similarities between OAS proteins and cGAS, and highlight their roles in antiviral immunity. Supplementary information The online version of this article (doi:10.1038/nri3719) contains supplementary material, which is available to authorized users.